Targeting MDSC activation via the RAGE/TLR4 pathway during early TB modestly reduces lung inflammation but not granuloma bacteria loads 2310052

Abstract

Abstract Introduction Tuberculosis (TB) causes more than a million deaths annually. Drug-sensitive TB is treated with an arduous antibiotic regimen taken for an extended duration but drug resistant TB is increasingly prevalent. Alternative treatments including host-directed therapies (HDTs) are being considered to shorten or improve conventional antibiotic therapy. Myeloid-derived suppressor cells (MDSCs) may inhibit immunity against the bacterium that causes TB, Mycobacterium tuberculosis (Mtb), and have been viewed as a HDT target for TB. Tasquinimod (TSQ) is a small molecule inhibitor of the RAGE/TLR4 pathway that has been tested in mice where it modestly reduced bacteria loads and inflammation, suggesting it may have value for TB treatment. More information on the role MDSCs play in TB and if they can be safely targeted to improve outcomes will help identify the value of this approach for treating TB. Methods Mtb-infected cynomolgus macaques were followed during early stages of TB, with TSQ treatment beginning at three weeks post infection for half of the animals and continuing for three weeks. During the study, blood was sampled for complete blood counts, chemistry panels, and plasma cytokine quantification, PET-CT scans were acquired at three weeks post-infection and prior to necropsy at six weeks, and bacteria loads were quantified from tissues post-necropsy. TSQ-treated and untreated control groups were compared to evaluate the effects of treatment. Results We found that TSQ treatment modestly, but not statistically significantly, reduced PET-measured lung inflammation, CT-measured granuloma size, and the rate of new granuloma formation. Plasma cytokine and bacterial LAM concentrations were equivalent between groups, but reduced concentrations of the neutrophil and MDSC-associated protein S100A9 were seen in the TSQ-treated group. Conclusion These data suggest that TSQ treatment may reduce inflammation without directly augmenting anti-Mtb immunity, shedding light on how MDSC function affects early TB. Funding Source NIH R01 AI164970 and AI184666 Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)